A long-acting methylphenidate transdermal formulation is available. As with any
transdermal system, drug delivery can vary greatly because of heat and site-related
skin porosity differences. AUC and Cmax can increase 300% if the patch is applied
to an inflamed area and 250% if the patch area is exposed to heat such as going
outside and exercising in the sun.
2,41–43 The patch is applied to the hip area for 9
hours, and methylphenidate is steadily released and absorbed into the circulation for
about 11.5 hours. When compared to the oral long-acting Oros release system,
methylphenidate’s side effects were similar between the two products but
numerically higher in the transdermal arm compared to the oral arm. One side effect
exclusive to the patch is skin irritation which can occur from 3% to 40%.
Amphetamines, including mixed amphetamine salts, dextroamphetamine, and
lisdexamfetamine, enhance the release of both dopamine and norepinephrine from
storage vesicles in the presynaptic neuron and block their storage in addition to
blocking their reuptake from the synaptic cleft. They also have a weak MAOI
Dextroamphetamine is metabolized via CYP2D6. A strong inhibitor of 2D6 could
increase levels twofold. The long-acting prodrug lisdexamfetamine requires
enzymatic hydrolysis in the blood to cleave off the L-lysine portion of the molecule.
This leaves just dexamphetamine available for activity.
rapidly absorbed, but the step of hydrolysis results in a delayed release of
dextroamphetamine in the circulation allowing for once a day dosing.
Since approximately two-thirds of children and adolescents with ADHD respond
equally to methylphenidate or amphetamine products, the preferred agent should be
based on duration of action, formulation preferences, and cost.
89-2, stimulant preparations are classified based on duration (i.e., immediate [2–5
hours], intermediate [6–8 hours], and long-acting [10–12 hours]) and available
delivery systems. Long-acting formulations are preferable to intermediate and short
acting, because it provides uninterrupted benefit allowing the child to avoid going to
the school nurse for doses or lack of effect between doses.
options are biphasic, which provides an immediate-release (IR) dose then a second
long-acting dose a few hours later. For example, Ritalin LA, Metadate CD, Focalin
XR, and Adderall XR all contain both immediate and enteric-coated, delayed-release
beads that mimic the blood concentrations seen with immediate-release stimulant
preparations given twice daily. Although a prescription methamphetamine product
does have FDA approval for treatment of ADHD, no expert guidelines recommend it
because of high-abuse liability and neurotoxicity.
Both types of stimulants are similar in their side effect profiles. Adverse drug
reactions such as insomnia and appetite loss are mild, and tolerance often develops
within a few days. These reactions can be easily managed by adjustment in dose and
timing if necessary (Table 89-3). In a double-blind, crossover study comparing side
effects of methylphenidate and dextroamphetamine, surveyed parents reported
worsening appetite (vs. baseline) with methylphenidate; severe insomnia and
appetite suppression were reported with dextroamphetamine.
significantly more severe with methylphenidate (vs. dextroamphetamine) included
insomnia, appetite suppression, irritability, proneness to crying, anxiety, dysphoria,
49 Only 3.2% of patients treated with either drug discontinued the
medication because of side effects. Another head-to-head trial showed similar types
and rates of adverse effects for IR methylphenidate and IR dextro/levo
Managing Adverse Effects of Stimulants Used in Children with Attention Deficit
Decreased appetite, nausea, or
Schedule evening meals after medication has worn off
Encourage foods with high caloric density or nutritionalsupplements
Encourage evening/bedtime snack
Switch from long-acting to short-acting preparation
Consider a drug holiday when appropriate
Sleep disturbance Administer doses earlier in the day
If using a sustained-release product, consider changing to a shortacting preparation
Discontinue afternoon/evening dose
Behavioral rebound If using short-acting preparation, consider changing to a long-acting
Irritability Assess time of symptoms:
Related to peak: reduce dose or try long-acting preparation
Related to withdrawal: change to long-acting preparation
Evaluate for comorbid diagnosis
Dysphoria, moodiness, agitation,
Decrease dose or change to long-acting preparation
Dizziness Monitor blood pressure
Lower dose or change to long-acting preparation to reduce peak
Development or increase in tic
Consider trial of clonidine or guanfacine
Consider referral to physician
There is an association between stimulant use and growth retardation. The relative
impact of this seems minimal and can be reduced or eliminated with drug
51–53 There seems to be no loss of efficacy if the child does have a drug
holiday and stops the medication over weekends holidays or summer months.
risk of drug holidays is a worsening of symptoms and this may have impact on social
There was concern that the stimulants may have a cardiotoxicity risk. Population
studies suggest, however, that the overall risk of sudden death associated with
stimulant use has been shown to be the same, if not lower, than that of the general
55 Slight increases in BP and HR are seen with methylphenidate and
amphetamines, although ECG changes are very rare.
56–58 Clinicians should follow
current recommendations suggested by the American Academy of Pediatrics and the
American Heart Association, which advocate screening for a personal or family
history of cardiovascular disease in all children with ADHD. Continual monitoring
for these risks along with routine blood pressure and heart rate assessments should
59 Pretreatment ECGs are not required but recommended by the AHA
as general practice for all children. Stimulants should not be used in those with
known structural cardiac abnormalities.
For patients with ADHD only, it is recommended to initiate treatment with either a
methylphenidate or an amphetamine.
2,32–34 For patients who fail both types of
stimulants or when stimulants are not preferred, a trial of a non-stimulant is
warranted (Table 89-2). Non-stimulants are less effective than stimulants and usually
require at least 4 weeks until a full response is evident. A meta-analysis of 29
It found that the effect size of amphetamine and methylphenidate was
significantly greater than that for atomoxetine, bupropion, and modafinil (p = 0.02).
If atomoxetine fails or is not indicated, the α2
-adrenergic agonists clonidine and
guanfacine should be considered.
Atomoxetine inhibits the presynaptic norepinephrine transporter and is classified as
norepinephrine reuptake inhibitor (NRI). Clinical trials have shown that atomoxetine
is superior to placebo in reducing the symptoms of ADHD in children, adolescents,
62,63 However, trials comparing atomoxetine with stimulants have found
atomoxetine to be less effective.
Atomoxetine is likely to have some immediate benefit after initiation but unlike the
stimulants a longer trial of 6 to 8 weeks is recommended as efficacy continues to
grow. Atomoxetine requires a 10- to 14-day titration to achieve a therapeutic dose of
1 to 1.5 mg/kg/day to avoid nausea (12%), vomiting (15%), and asthenia (11%).
with stimulants, atomoxetine can also raise blood pressure and heart rate, with
reports of high systolic and diastolic blood pressures occurring in 8.6% and 5.2% of
pediatric subjects, respectively. Increases in heart rate of more than 110 beats/minute
and more than 25 beats/minute above baseline were observed in 3.6% of patients.
Atomoxetine is metabolized via CYP 450 2D6, with the major metabolite being 4-
hydroxyatomoxetine which is also a potent inhibitor of NE reuptake but at low
concentration levels. It has a half-life of 4 to 5 hours but can be extended by about 3
There have been postmarketing cases of reversible hepatic injury in association
with atomoxetine, but this is quite rare.
70 Baseline liver enzyme testing should be
performed, and evidence of jaundice or liver injury should warrant immediate
discontinuation. Atomoxetine also contains the warning regarding increased risk of
atomoxetine group was 5/1,357 (0.37%) and placebo group was 0/851 (0%).
despite the low risk, monitoring frequently for the first 3 months of treatment is
Clonidine and guanfacine are α2
-agonists that have been used for years off-label to
control hyperactive/impulsive or aggressive symptoms and insomnia.
believed to directly stimulate the postsynaptic norepinephrine receptors in the
prefrontal cortex and locus coeruleus. Guanfacine is most specific for the α-2a
receptor, while clonidine is less specific and agonizes α-2a, b, and c. The FDA has
approved extended-release formulations for clonidine and guanfacine both as
monotherapy and as adjuncts to stimulants. Clonidine and guanfacine are also
approved as adjuncts to stimulants for ADHD. Although they are a monotherapy
option, they are not considered as first line as they are less effective than stimulants.
They are particularly useful for behavioral comorbidities, such as aggression and
Guanfacine is primarily metabolized via CYP 3A4, and potent inhibitors can
increase blood levels by 200%. Guanfacine extended release provides
approximately 60% of the serum levels of the immediate-release version. Clonidine
is partially metabolized via CYP 2D6, although inhibitors of this pathway have only
minor changes in serum levels.
76 The extended-release version has an AUC
approximately 89% of the immediate release.
The side effect profile of α-2 agonists is quite different than the stimulants and
atomoxetine. Sedation and related side effects can occur in nearly 40% for both.
Reductions in BP and HR can occur and need to be monitored. Bradycardia (HR <
60 bpm) can occur in up to 20% of children with clonidine and is a side effect of
guanfacine also but to a lesser degree. This is likely because of guanfacine’s
specificity to α 2a. Rebound hypertension can occur if either of these medications are
Despite positive studies with immediate-release formulations, the short duration of
action makes them less desirable than the QD dosing of guanfacine ER and the BID
dosing clonidine extended-release formulation.
Either stimulant groups are considered first line and in this case methylphenidate
10 mg qam is tried. After steadily increasing the dose to 30 mg qam the parents feel
that there is minimal change in attention, but that there are significant side effects of
CASE 89-1, QUESTION 5: What would be the next trial of medication for M.T.?
Expert guidelines state that if medication is decided upon then the greatest efficacy
is from the stimulants. Neither stimulant is considered superior to the other and initial
choice should be based on the comfort level of the clinician and patient/parent
acceptance. If the initial choice of stimulant is ineffective, it is recommended to trial
the other stimulant class. By doing this 90% of children will display efficacy.
Therefore, the next trial for M.T. should be the initiation of dextroamphetamine 5 mg
qam and titrate as tolerated to a maximum of 40 mg a day.
CASE 89-1, QUESTION 6: M.T. is showing some improvement on 10 mg qam of immediate-release
the next step of pharmacotherapy for M.T.?
Increasing the dose to 30 mg qam is possible. Although a switch from a stimulant
to atomoxetine could be tried, data have shown that atomoxetine is less effective than
stimulants. Experts recommend that combination therapy of a stimulant and an α-2
agonist is appropriate, and studies have shown an increase in efficacy from
monotherapy to combination therapy.
TOURETTE’S SYNDROME AND TIC DISORDER
Tourette’s syndrome is neuropsychiatric condition which has tics as a hallmark
symptom. Children with ADHD have a higher risk of comorbid tic disorder than the
general population; however, stimulants are relatively safe in this population. As an
example, the Tourette’s Syndrome Study Group contrasted the effect of
methylphenidate, clonidine, and the combination of the two to placebo in the
treatment of 136 children (7–14 years old) diagnosed with ADHD and Tourette
77 The group concluded that prior recommendations to avoid
methylphenidate in these children because of concerns of worsening tics were
unsupported. As such, expert recommendations are that a child with ADHD should
start on methylphenidate, and if tics emerge or worsen then a switch to atomoxetine
or clonidine is warranted. A meta-analysis of studies with subjects who have ADHD
and Tourette’s syndrome concluded that methylphenidate shows the greatest
improvement in ADHD symptoms without worsening tics in most kids. α-2 Agonists
offer less efficacy in ADHD symptoms but greater control over tics compared to
methylphenidate. Atomoxetine offers benefit on both groups of symptoms and is an
32,74,75 Amphetamines should be avoided because although they do treat ADHD
symptoms, they have a higher chance of worsening tics compared to
A review regarding treatment of tic disorders without comorbid ADHD states that
the α-2 agonists guanfacine and clonidine are recommended as first-line options.
Guanfacine may be preferred because of less sedation than clonidine.
Anxiety disorders are more frequently comorbid in the ADHD child (approximately
ninefold) and adult (approximately fourfold) compared to the frequency seen in the
general population. Despite the fact that the anxiety disorder may be a separate
illness, anxiety symptoms in the child can be directly related to poor performance
because of ADHD symptoms. Treatment with a stimulant that subsequently improves
performance will reduce the anxiety. However, some children after a trial with a
stimulant will not have an anxiety reduction or it may even worsen. At this point a
trial with atomoxetine is recommended over treating the anxiety with an SSRI and
Despite the fact that stimulants are medications with an abuse risk, multiple studies
have shown a protective effect against developing a substance-use disorder with
80 Using a stimulant for ADHD in a
current substance abuser has contradictory results. Stimulants do treat the ADHD
symptoms but not as robustly as those without a concurrent substance-use disorder.
They do not seem to reduce the substance use but clearly do not worsen it.
opinion suggests that those with current substance-use disorders should be tried on
non-stimulant options first, but stimulants are not fully contraindicated and can be
used with close monitoring. There is growing data to support that there is a high rate
of diversion of stimulants in the college population. One report correlated an
increased incidence of diversion with increased difficulty of the academic
If misuse and diversion are of concern, methylphenidate comes as a transdermal
patch formulation, and dextroamphetamine is available as a hard to abuse prodrug
Despite the potential for being less effective than a stimulant, atomoxetine has
preferred benefits in specific patient subtypes. Because it is not a stimulant, its risk
of abuse and diversion are low and is preferred in patients with an addictions
disorder history or living in a household where someone other than the patient (e.g.,
parent or sibling) has an addiction disorder and may take the patients medications.
Stimulants may cause psychosis. This is because of the enhancement of DA centrally.
If the child is acknowledging hallucinations or exhibiting bizarre behavior then
cessation of the stimulant is required. A rechallenge can occur but at a lower dose. If
a child stabilized on the medication starts to exhibit psychotic symptoms then one
should assess for drug interactions. The methylphenidate transdermal patch
formulation can have greater unexpected fluctuations in blood levels because of a
greater range of absorption compared to the oral formulations.
the transdermal patch is influenced by placement site and temperature of the skin.
Treating this side effect with an antipsychotic is not recommended.
Bupropion has been shown to be effective compared to placebo, but it is less
effective than stimulants in treatment of ADHD.
67 Randomized, controlled trials have
established the effectiveness of bupropion as an alternative to the psychostimulants in
the treatment of ADHD in children, adolescents, and adults.
common adverse effects encountered with bupropion in ADHD studies were
dermatologic reactions and seizures. Dermatologic reactions occurred twice as often
with bupropion compared with placebo. Severe bupropion-induced urticaria
required discontinuation in 5.5% (4 of 72) of the patients in one study.
risk of seizures increases by about fourfold if extended-release doses of greater than
450 mg/day or greater than 400 mg/day sustained-release doses of bupropion doses
88 Although there are no case reports of seizures in children receiving
therapeutic doses of bupropion, it is recommended to limit doses to less than 6
mg/kg/day in the treatment of ADHD and to avoid using bupropion in patients with a
Modafinil has been found to be effective in the treatment of prepubescent, adolescent,
89,90 The 2006 Pediatric FDA advisory committee
reviewed the efficacy and safety of modafinil for ADHD and determined the drug
was effective but rejected its approval for ADHD based on concerns about safety.
Twelve of 933 patients developed a skin rash, with one case thought to be Stevens–
TRICYCLIC ANTIDEPRESSANTS (TCAS) AND SEROTONIN AND
NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS)
As recently as 2007 guidelines reported, TCAs could be an option for ADHD.
However, their poor tolerability and dangerous effect on cardiac conduction has
resulted in more recently published guidelines in 2011 and 2014 to not recommend
The SNRI venlafaxine has shown efficacy in both adolescents and adults with
ADHD. This is a legitimate choice for comorbid anxious or depressed older patients,
but because of antidepressants having a risk of increasing suicidal thinking in
children, other options should be tried first. Adults often have this comorbidity and
venlafaxine in that population is more likely to be used.
There have been a number of studies that have tried to discern if certain diets may
result in ADHD. One of the most famous regimens is the Feingold Diet. Recent
reviews on the topic have found the evidence to be of low quality and of small
benefit. Most studies have not been blinded and when efficacy is noted it is of lower
rates than the FDA-approved pharmacotherapies. Additionally, there is a practical
limitation to the implementation of these diets as it eliminates many of the foods that
are regular parts of American meals. At this time it does seem reasonable to assume
that some children’s ADHD-like behavior may be related to intolerance to certain
dyes, artificial sweeteners, and flavors. One should not discourage a parent to
promote healthier food selection for their child, but the effectiveness of lowering
their symptoms is marginal. Additionally, if a child has a delay in administration of
pharmacotherapy because of trials of different types of diets then this could result in
persistency of symptoms longer than is necessary.
Many companies have created dietary supplements that have been touted as
effective remedies for treating and preventing ADHD, but convincing results derived
from rigorous trials are currently lacking and are likely to benefit a very few children
with food allergies or intolerances.
92–94 For instance, the use of very high doses of
vitamins or minerals has been promoted as a possible intervention, but all
randomized, controlled trials conducted to evaluate the effectiveness of megavitamin
therapy have been negative to date.
95 Omega-3 fatty acids have been considered as
possible treatments for ADHD, based largely on population studies demonstrating an
association between high dietary intake and a reduced risk of various
neuropsychiatric disorders. Omega-3 supplementation, specifically EPA content, may
have a small benefit as monotherapy. Studies of omega-3 as an adjunct to stimulants
have shown little added benefit.
96,97 Similarly, there have been reports of zinc, iron,
magnesium, Hypericum (St. John’s wort), and gingko all relieving ADHD symptoms,
but the evidence to support these interventions is very limited at the present time.
There have been other somatic treatments aimed at relieving ADHD symptoms that
may prove to be beneficial in the years ahead.
98 Several small randomized studies
have reported benefits with neurofeedback, in which children are trained to modify
certain brain activities demonstrated on electroencephalographic tracings (e.g.,
increased slow wave or α activity). Preliminary evidence also supports the
exploration of meditation as an effective
intervention for ADHD, particularly mindfulness-based methods that have proven
to be particularly helpful for depression and chronic pain conditions.
interventions have included cognitive-behavioral therapy, social skills training
programs and computer-based cognitive training programs. Early studies of some of
these intervention strategies have been promising and there is need for further
research to establish efficacy.
35 Regarding acupuncture a recent systematic review
failed to find any studies of sufficient rigor to include in their analysis.
failed to find any studies of sufficient rigor to include in their analysis.
QUESTION 1: K.C. is a 27-year-old female who is an adjunct professor in a pharmacy program and comes
treatment recommendations for an adult with ADHD?
It is estimated that two-thirds of children with ADHD will continue to have
significant symptomatology as adults.
11 Often the hyperactivity/impulsivity aspect of
the illness becomes less pronounced once the child hits adolescence, but the
symptoms of inattention persist into adulthood.
6 Even though many of the children
with ADHD may no longer satisfy strict diagnostic criteria for ADHD as adults, the
severity and persistence of inattentive symptoms can continue to cause considerable
social and functional disability. One investigation followed 128 children with
ADHD for several years and reported that hyperactivity and impulsivity symptoms
were seen to decline at a higher rate than inattention symptoms.
have followed children with ADHD to adulthood by comparing the academic records
of control subjects and ADHD adults. The latter had significantly higher rates of
repeated grades, tutoring, placement in special classes, and reading disability.
Children with ADHD will have greater morbidity in psychosocial and educational
areas in adulthood compared to adults who did not have ADHD as children.
with ADHD have been found to achieve lower socioeconomic status and experience
more work difficulties and more frequent job changes.
reported more psychologic maladjustment, more speeding violations, and more
frequent changes in employment.
105 More adults with ADHD had their driver’s
licenses suspended, had performed more poorly at work, and had quit or been fired
from their job. Adults with ADHD were also more likely to have had multiple
The diagnostic criteria for ADHD in adults are the same as for children and
4 However, only five of either hyperactivity/impulsivity or
inattention must be present for a minimum of 6 months, impairing function in two or
more settings. A diagnosis of ADHD in adults also requires evidence that symptoms
were present before the age of 12. One study compared the functional outcomes of
adults with ADHD before age 7 with adults, who had the requisite symptoms but
lacked conclusive evidence of childhood onset. The investigators found no difference
between the two groups in primary outcomes such as learning disabilities, arrests,
motor vehicle accidents, and divorce.
Current treatment recommendations for ADHD in adults continue to support
pharmacotherapy as the first-line option for moderate-to-severe symptoms.
Although benefits have been noted for psychotherapeutic approaches such as
cognitive behavioral therapy and dialectic behavioral therapy, these interventions are
recommended only for adults exhibiting suboptimal response to approved
A variety of medications have been reported to be beneficial for ADHD in adults,
including methylphenidate, dexmethylphenidate, mixed amphetamine salts,
lisdexamfetamine, desipramine, bupropion, atomoxetine α-2 agonists, venlafaxine,
85,90,109–116 The stimulants and atomoxetine are FDA approved in
In general, the effect sizes for these ADHD medications in adults have been
very similar to what has traditionally been reported in children. A meta-analysis of
medications for ADHD in adults found that long-acting stimulants were significantly
more effective than non-stimulant drugs, but that the effectiveness of shorter-acting
stimulants was comparable to the latter.
9 The authors also noted that lower doses
appeared to be more effective for inattention than hyperactivity. For example, doses
for immediate-release methylphenidate were more conservative (0.3 mg/kg per dose
in adults) when inattention was the predominate feature. In contrast, doses of up to
0.6 mg/kg immediate-release methylphenidate were often necessary to optimally
control the behavioral feature of the disorder in children.
doses are consistent with 0.5 to 1.0 mg/kg/day doses found to be effective in
110 Mixed amphetamine salts were effective in doses of 20 to 60 mg/day.
The effective dose of desipramine was approximately 150 mg/day.
generally dosed at 3 mg/kg/day.
85 The two large studies of atomoxetine used doses
that ranged from 60 to 120 mg/day.
114,115 The mean effective dose for modafinil was
Treatment with stimulants or atomoxetine have shown improvements in reduced
criminality and driving accidents.
These double fills are also written by two different physicians.
What would be an appropriate response by the pharmacist to K.C.’s request?
As noted above, ADHD symptoms can persist into adulthood for many children. A
positive history of either an ADHD diagnosis or untreated symptoms in childhood is
required for an adult to be diagnosed with ADHD. However, many other diseases
can lead to a false positive. Complete blood counts, urine toxicology, and head injury
must all be evaluated along with psychiatric conditions such as bipolar disorder,
anxiety disorders, and major depressive disorder.
122 Also, one cannot rule out the
possibility of substance-use disorder. As with other drugs that have an abuse
liability, stimulants can either be abused by the patient or diverted and sold to those
who want to use them for their euphoria-inducing effect instead of helping treat
ADHD. There is an increasing amount of data reporting the intermittent use of
stimulants by college students for study enhancement and abuse, particularly when
mixed with a sedating drug of abuse. Therefore, the pharmacist should consult with
the clinician who wrote the prescription alerting him to the recent fill at another
pharmacy. It is quite possible that this new prescription is legitimate, but it is also
possible that K.C. is misusing the dextroamphetamine herself or diverting them to
others. A reevaluation of her diagnosis is necessary. If it is confirmed that the patient
does have ADHD then options would be to switch to a less abusable stimulant such
formulations are less abusable they are not devoid of abuse risk. Atomoxetine or the
non-FDA adult approved agents such as α-2 agonists or bupropion, venlafaxine, and
modafinil will likely be less effective than the stimulant for ADHD but provide a
A full list of references for this chapter can be found at
http://thepoint.lww.com/AT11e. Below are the key references and websites for this
chapter, with the corresponding reference number in this chapter found in parentheses
Psychopharmacol. 2014;1–25. (32)
Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA). Canadian ADHD Practice
Guidelines. 3rd ed. Toronto, ON: CADDRA; 2011. (34)
American Academy of Child and Adolescent Psychiatry. http://www.aacap.org.
National Alliance on Mental Illness. http://www.nami.org.
National Institute of Mental Health. http://www.nimh.nih.gov.
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